Alzheimer' s disease (AD) represents one of the most important and challenging public health concerns that will affect this country in the coming decades, since it most severely affects the fastest growing segment of our population: individuals age 85 and older. The ability to identify nondemented older adults who are in a preclinical phase of AD will have far-reaching implications for both improved early diagnosis and use of anti-dementia pharmacologic therapies. Such drugs treatments aimed at slowing the progression of AD ('neuroprotection') will be most effective if applied at the earliest stages of AD before significant neuronal losses have occurred, which provides an important rationale for making accurate preclinical diagnoses of AD. However, one of the remaining obstacles to such efforts centers on the difficulty in accurately identifying individuals with incipient AD before their deficits become clinically apparent (i.e., prior to both cognitive and functional decline). We propose to recruit and follow a group of nondemented older adults at high risk for AD in an effort to better detect and characterize its preclinical stage. Individuals age 85 and older (oldest-old), and individuals with the E4 allele of the apolipoprotein E gene (ApoE), both have significantly elevated risks of developing AD. However, advanced age or ApoF E4 genotype alone are insufficient in determining who will develop AD. We propose to conduct a five-year longitudinal study of the oldest-old in which the combination of neuropsychologic, neuroimaging, and genetic assessments will be examined, relative to the young-old (ages 65-75), in an effort to identify the most salient preclinical markers of AD. Because the underlying neuropathologic changes in AD may differ between the young-old and the oldest-old, a secondary goal will be to determine the unique patterns and contributions of these multi-modal assessments to the diagnosis of AD in the oldest-old. The proposed study will (a) examine the utility of neuropsychologic, magnetic resonance (MR) morphometric, and genetic susceptibility markers in order to determine the pattern of impaired brain structures and processes associated with the preclinical phase of AD in the oldest-old; and (b) conduct exploratory analyses to determine whether our neuropsychologic measures are associated with early structural abnormalities (as detected by MR imaging and neuropathologic indices) in at-risk individuals. Improving our ability to detect AD preclinically will be of critical importance for the oldest-old, who are the fastest growing high-risk population. Furthermore, an improved understanding of the brain mechanisms associated with the earliest cognitive changes in at-risk groups will advance our ability to target those who stand to benefit most from early pharmacologic intervention.